Ester derivatives of 1-halo-1,1,2,3-propane tetracarboxylic acid

ABSTRACT

Novel polyfunctional compounds and a novel process for their preparation are disclosed. These compounds may be converted into the acid or salt forms of cis and trans aconitic acids as well as into a racemic mixture of isocitric acid, alloisocitric acid and the lactones of isocitric acid and alloisocitric acid and their salts. All of the acid and salt forms produced are useful as metal sequestrants and/or detergent builders. The novel polyfunctional compounds can also be saponified to their corresponding alkali metal salts which, in turn, are also metal ion sequestering agents and detergent builders. The polyfunctional compounds are the reaction products obtained from the reaction of selected salts of monoalkyl esters of maleic acid with selected active hydrogen containing compounds.

This is a Divisional, of application Ser. No. 642,850, filed Dec. 22,1975, now U.S. Pat. No. 4,123,458.

This invention broadly relates to novel polyfunctional compounds and aprocess for their preparation. The novel compounds may be converted intocis and trans aconitic acid and into a racemic mixture of isocitricacid, alloisocitric acid and the lactones of isocitric acid andalloisocitric acid. These compounds may also be saponified to formalkali metal salts corresponding to the particular compound employed.These salts, in turn, are metal sequestering agents and/or detergentbuilders. In the preferred embodiments the polyfunctional compounds areconverted into either cis and trans aconitic acid or into a racemicmixture of isocitric acid, alloisocitric acid and the lactones ofisocitric acid and alloisocitric acid and cis and trans aconitic acid,are useful as food acidulants and metal ion sequestrants. The alkalimetal, ammonium and substituted ammonium salts of isocitric acid,alloisocitric acid and cis and trans aconitic acid have utility both asmetal ion sequestrants and detergent builders.

The reaction of active hydrogen compounds with unsaturated esters suchas esters of maleic acid is known and is generally accomplished by meansof the well known Michael reaction. This reaction is consideredthoroughly in Chapter 3 of Volume 10 of the publication entitled"Organic Reactions" edited by Roger Adams et al and published in 1959 byJohn Wiley & Sons Inc. In its original sense, as described in thepublication, this reaction involves the addition of a donor moietycontaining an alpha-hydrogen atom in a system ##STR1## to acarbon-carbon double bond which forms part of a conjugated acceptorsystem of general formula ##STR2## The addition proceeds under theinfluence of alkaline or basic catalysis.

Inherently in the Michael reaction, the donor moiety, under theinfluence of the basic catalysis (sodium metal is a catalyst of choice)forms an anion which in turn reacts with the beta carbon of the acceptorsystem. Through the use of this reaction a series of compounds have beenprepared. A listing of a large number of these reactions and reactionproducts appears on pages 271-544 of the above-mentioned publication.The reaction in certain selected instances does not require an addedcatalyst because one of the reactants contains its own basic function.The Michael reaction, thus, is extremely useful for the synthesis ofselected compounds. However, disadvantages arise in attempting toprepare certain mixed esters by this route because oftransesterification which can take place under the conditions of theMichael reaction thereby producing mixtures of mixed esters incorrespondingly diminished yield rather than a single mixed ester inrelatively high yield. Further, reverse Michael reactions can occur toproduce rearranged starting reactants. The resulting mixtures arenormally extremely difficult to separate. These difficulties, thus,militate strongly against the use of the Michael reaction and indeed theapplicability of this reaction for desired mixed ester products. Inparticular, with reference to the preferred preparations of aconiticacid and the mixture of isocitric acid, alloisocitric acid and theirlactones in this invention, prior art processes were practically limitedto natural fermentation. Although some synthetic methods have beenproposed in the literature such as in the articles by Michael, J. pr.Chem. 49 (ii), 21 (1894), Pucher and Vickery, J. Biol. Chem. 163 169-184(1946) and Gawron et al., J.A.C.S. 80 5856-5860 (1958), none of thesemethods appear to have been commercialized.

Accordingly, an object of the present invention is to provide a processfor producing novel mixed ester compounds by adding an active methyleneor an active methine compound across the double bond of selected saltsof maleic acid esters, wherein the reverse Michael reaction issubstantially inhibited and wherein the reaction takes place in theabsence of added alkaline catalyst.

A further object is to produce a novel polyfunctional compound which maybe converted into cis and trans aconitic acid or into a mixture ofisocitric acid, alloisocitric acid and the lactones of isocitric acidand alloisocitric acid as well as salts of these acids.

Yet another object is to provide a novel method for preparing novelpolyfunctional compounds which can be converted into metal ionsequestrants and detergent builders.

Other objects and advantages will appear as the description proceeds.

The attainment of the above objects is made possible by this inventionwhich includes novel polyfunctional compounds as well as a process fortheir preparation. These novel compounds have the general formula (I) asfollows: ##STR3## wherein R is a primary alkyl group of one to fourcarbon atoms and preferably a methyl or ethyl group,

wherein M₁ is hydrogen, calcium, magnesium, strontium, barium, sodium,potassium or lithium,

wherein x is 1 or 2 and is equivalent to the valency of M₁,

wherein Q is preferably H but in alternative embodiments may alsorepresent a primary alkyl group of 1 to 4 carbon atoms

wherein Z is phenyl; substituted phenyl having electron withdrawingsubstituents on the ring such as, for example, chlorine, bromine andnitro; cyano (--CN); ##STR4## nitro (--NO₂) or a carboxylic ester(--COOR₂) wherein R₂ is a primary alkyl group containing 1 to 4 carbonatoms, preferably a methyl or ethyl group, and

wherein Y is dependent on Z and when Z is a carboxylic ester (COOR₂), Yrepresents a carboxylic moiety (COOR₁) wherein R₁ is a lithium, sodiumor potassium cation or a primary alkyl group containing from 1 to 4carbon atoms and preferably a methyl or ethyl group, cyano (--CN) and##STR5## when Z is a cyano, phenyl or substituted phenyl group, Yrepresents cyano (--CN); and when Z is nitro (--NO₂), Y is hydrogen ormethyl.

Additionally, the above objects are attained by the novel process ofthis invention to prepare the polyfunctional compounds of formula (I).

PROCESS FOR PREPARING THE NOVEL POLYFUNCTIONAL COMPOUNDS

This process is preferably substantially anhydrous and includes reactingby heating a salt of a monoalkyl ester of maleic acid with an activemethylene or methine containing compound which is also referred toherein as the active hydrogen containing compound. The monoalkyl estersalt of maleic acid is of the general formula (II): ##STR6## in which Rand x are as previously defined and M represents calcium, magnesium,strontium, barium, sodium, potassium or lithium. In this process in thecompound of formula (II) M cannot represent hydrogen whereas in formula(I) M₁ can represent hydrogen as well as the cations represented by Mand thus the two separate designations of M and M₁ are utilized. Theactive hydrogen containing compound is of the general formula (III):##STR7## in which Y, Q and Z are as previously defined.

The salts of the monoalkyl ester of maleic acid [formula (II)] employedin the process of this invention are prepared by treating a monoalkylester of maleic acid with a base. The monoalkyl ester of maleic acid isin turn readily available by reacting maleic anhydride with a loweralkyl alcohol having 1 to 4 carbon atoms, for example, methanol,ethanol, propanol and butanol. More specifically, maleic anhydride maybe dissolved in the alcohol either at room temperature or by heating atan elevated temperature, e.g. about 50° C. to 60° C. Addition of theappropriate base, i.e. alkali metal or alkaline earth metal hydroxidesuch as sodium or potassium hydroxide or magnesium, barium, strontium orcalcium hydroxide to a pH of about 7 to 9, neutralizes the acid portionof the molecule to produce the desired salt of formula (II). Themonoalkyl maleate salt thus prepared is separated from the reactionmixture by conventional techniques, e.g. distilling off the alcoholunder reduced pressure, or crystallization from the appropriate alcohol.

The active hydrogen containing compounds of formula (III) are knowncompounds. Malonate esters such as, for example, diethyl malonate anddimethyl malonate and cyanoacetate esters such as, for example, methylcyanoacetate and ethyl cyanoacetate are preferred.

The subject invention, encompassing novel compounds and a novel processfor their preparation, overcomes one or more of the disadvantages of theprior art heretofore described. This is accomplished with the advantagethat such compounds may be easily prepared in good yields suitable forsubsequent conversion into metal sequestering agents and, preferably,into either cis and trans aconitic acid or a mixture of isocitric acid,alloisocitric acid and the lactones of isocitric acid and alloisocitricacid.

The invention is hereinafter set forth in more details, specificfeatures thereof being particularly delineated in the appended claims.

In the practice of the present invention a compound of formula (II)above is reacted preferably under substantially anhydrous conditionswith a compound of formula (III) at an elevated temperature to form areaction product which is the polyfunctional compound of formula (I)except for the cases wherein M₁ =H. The latter compounds are obtainedwith an additional step involving acidification as will be more fullydescribed hereinafter.

Since the ester group of the mono maleic ester salt (formula II) canhydrolyze in the presence of moisture to produce a non-reactive species(i.e. a mono salt of maleic acid), the reaction is preferably run undersubstantially anhydrous conditions. This can be accomplished bypre-drying the reactants and any reaction solvent by conventional meansbefore carrying out the reaction.

Generally, the reaction of the compounds of formulae (II) and (III) toproduce the novel compounds of formula (I) proceeds at temperatures ofabout 25° C. to 200° C. and more preferably between about 100° C. and160° C. The actual reaction temperature will depend on whether a solventis employed and the mutual solubilities of the reactants. Thus, ifdimethyl formamide is utilized as the reaction solvent or co-solvent, atemperature as low as room temperature (about 25° C.) to about 100° C.can be utilized whereas if the active hydrogen containing compound offormula (III) is utilized in excess as both solvent and reactant, highertemperatures up to about 200° C. may be employed. Generally while refluxtemperatures are normally operable, it is desirable to keep thetemperature in the range of about 100° C. to 160° C. to maintainreasonable reaction rates and to avoid the reverse Michael reaction andother decomposition reactions which tend to take place at the highertemperatures.

The time necessary to complete the reaction is not critical. It willdepend on temperatures, on the nature of the reactants, the solventused, if any, concentration of the reactants and the homogeneity of thesystem. Generally about one to three hours is sufficient to obtain themaximum yield.

The reaction takes place preferably in the liquid phase. Generally, theactive hydrogen containing compound of formula (III) is a liquid andwill dissolve the ester salt compound of formula (II). Since an excessof the reactant of formula (III) is beneficial to the reaction, such asexcess is preferred as side reactions are minimized and eventualseparation of the components is easier. Suitable active hydrogencompounds of formula (III), e.g. dimethyl malonate, methyl sodiummalonate, diethyl malonate, dipropyl malonate, dibutyl malonate, phenylacetonitrile, methyl cyanoacetate, ethyl cyanoacetate, nitroethane andthe like may be utilized. Additionally, a co-solvent for both reactantsmay be used instead of an excess of the formula (III) compound providedthe co-solvent does not contain an active hydrogen which will competewith the formula (III) compound under the reaction conditions andprovided the co-solvent dissolves the reactants sufficiently tofacilitate the reaction. Suitable solvents are, for example,dimethylformamide, dimethylacetamide and dimethyl sulfoxide.

The desired reaction product (i.e. a compound of formula I) can bereadily recovered from the reaction mixture by conventional methods suchas for example by adding an insolubilizing liquid, e.g. ethyl ether.Upon the addition of a sufficient amount of such an insolubilizingliquid, the product precipitates out of solution and is readilyseparated from the reaction media by conventional means. The recoveredproduct is sufficiently pure for conversion into the corresponding metalsequestrant salt. Upon filtration or vacuum distillation, washing,recrystallization if desired and drying, the desired product may beobtained in purer form. Alternatively, the acid form of the reactionproduct may be isolated by treating the reaction product with an aqueoussolution of a mineral acid to liberate the carboxylic acid (M₁ =H informula I) which is readily separated from the aqueous layer byextraction with a suitable solvent such as ethyl ether or by filtrationin those cases where the carboxylic acid is a solid.

The present invention thus permits the synthesis of the desiredpolyfunctional compound of formula (I); further, in certain cases suchcompounds are produced in good yields. An additional advantage of thisinvention is that the novel products are obtained in readily recoverableform and that the novel synthesis or process permits the formation ofthe product without the use of added catalyst.

HYDROLYSIS OF SELECTED POLYFUNCTIONAL COMPOUNDS TO PRODUCE METAL IONSEQUESTRANTS AND DETERGENT BUILDERS

The compounds of formula (I), with the exception of those cases whereinZ is a nitro group, may be hydrolyzed under basic conditions to obtainthe salt forms of the compounds represented by formula (IV) below. Theacid forms of the compounds of formula (IV) are obtained by conventionalacidification of the salt forms produced by the basic hydrolysis.Formula (IV) is as follows: ##STR8## wherein Z, Q and Y are aspreviously defined and wherein M₁ represents hydrogen, sodium,potassium, lithium, calcium, magnesium, barium or strontium and x is 1when M₁ is hydrogen or alkali metal and 2 when M₁ is alkaline earthmetal. In those cases wherein Y and Z are carboxylic functions, i.e.--COOR₁ and --COOR₂ or a cyano group, alkaline hydrolysis converts eachof the groups to a --COOM₁ ^(+x) function wherein M₁ is an alkali metalor alkaline earth metal cation and x is as previously defined.

The alkaline hydrolysis is accomplished by heating the compounds offormula (I) with a stoichiometric amount or a slight excess of an alkalimetal hydroxide, an alkaline earth metal hydroxide or an alkali metalcarbonate in aqueous or aqueous alcoholic media. The hydrolysis iscarried out at a pH of about 9-12, preferably about 10-11 and at atemperature of about 25° C. to about 100° C., preferably about 40° C. toabout 60° C. The preferred temperature and pH ranges in the hydrolysisprocedure are used to maintain reasonable reaction rates and to minimizereverse Michael reactions.

Isolation of the salt forms of formula (IV) obtained by the abovealkaline hydrolysis is carried out by conventional techniques such assolvent precipitation, evaporation, drying and recrystallization fromsuitable solvents such as alcohol-water.

In the cases where the alkaline earth metal salts of formula (IV) areproduced, these may be converted into the alkali metal salt form bytreatment with an aqueous solution of an alkali metal carbonate whichprecipitates the alkaline earth metal cations as the insolublecarbonate. The latter is then removed by filtration and the alkali metalsalt of formula (IV) is isolated from the filtrate by conventionalmethods as previously described above.

Both the alkali metal and alkaline earth metal salt forms of formula(IV) may also be conventionally treated with a cation exchange resin toproduce the acid forms of formula (IV) which may then be isolated byconventional methods such as extraction with a suitable solvent followedby evaporation of the solvent from the extract.

The acid forms of formula (IV) may be utilized as such (e.g. as metalion sequestrants) or converted in the desired salt forms or mixture ofacid and salt forms by neutralization with the required amount of thedesired alkali metal hydroxide, ammonium hydroxide, an organic aminesuch as mono-, di- and tri-ethanolamine, morpholine and mixturesthereof. As previously indicated the alkali metal, ammonium andsubstituted ammonium salt forms of formula (IV) have utility as metalion sequestrants and detergent builders.

CONVERSION OF SELECTED HYDROLYZED POLYFUNCTIONAL COMPOUNDS INTOTRICARBALLYLIC AND SUPSTITUTED TRICARBALLYLIC ACIDS AND THEIR SALTS

In the cases where the compounds of formula (IV) have the structure##STR9## wherein Q is as previously defined, these compounds may bedecarboxylated by heating alone at atmospheric pressure or under vacuumat temperatures greater than about 75° C., preferably about 75° C. to175° C., depending on the decomposition point of the particularcompound. Alternatively, decarboxylation of these compounds may beaccomplished by heating the compounds with a dilute mineral acidsolution, e.g. hydrochloric acid, at a pH of less than about 2 and underatmospheric pressure. These decarboxylation procedures producetricarballylic acid and substituted tricarballylic acids having theformula ##STR10## These acids may be neutralized with bases such asalkali metal hydroxides, ammonium hydroxide and alkylolamines to producemetal ion sequestrants and detergent builders.

ESTERIFICATION OF THE POLYFUNCTIONAL COMPOUNDS TO PRODUCE MIXEDPOLYESTER COMPOUNDS

In the case of the compounds of formula (I) wherein M₁ is H, thesecompounds may be completely esterified to produce mixed polyestercompounds. This is accomplished by conventional reactions such as

1. reaction with diazomethane or

2. reaction with thionyl chloride followed by reaction with a normalalkanol of 1 to 12 carbons.

The products produced have the formula: ##STR11## wherein R₃ is a normalalkyl group of 1 to 12 carbon atoms and wherein R, Z, Q and Y are aspreviously defined except that in the case where a cyano group isinitially present it also becomes converted in the process scheme of 2above to COOR₃. Similarly in those cases where Y is COOR₁ and R₁ is H,sodium, potassium or lithium, Y is converted to COOR₃.

HALOGENATION OF SELECTED POLYFUNCTIONAL COMPOUNDS

The compounds of formula (I) having the structure ##STR12## wherein R,R₁ and R₂ are as previously defined, can be halogenated withhypochlorous acid, hypobromous acid, sodium hypochlorite, sodiumhypobromite, chlorine or bromine in aqueous or mixed aqueous/methanolicsolution at pH's from about 2 to 8 to produce novel compounds having thefollowing formula: ##STR13## or salts thereof and wherein R, R₁ and R₂are as previously defined and are preferably methyl or ethyl and Q₁ isBr or Cl and preferably chlorine.

The halogenation process is preferably carried out in an aqueousreaction medium. The compound of formula (IA) is introduced into areaction vessel with water and, while stirring the mixture, a solutionof a compound capable of generating HOX (wherein X=Cl or Br) is slowlyadded. The amount of reaction medium (i.e. water) used is not criticaland is generally from about 50 to about 95% by weight of the totalinitial reaction mixture (i.e. compound IA plus water). The HOX requiredis conveniently generated from an alkali metal or alkaline earth metalhypohalite by acidification with a mineral acid solution such ashydrochloric or hydrobromic acid. Sodium hypochlorite or sodiumhypobromite solutions are readily available as 5-15% solutions and arereadily employed in this process. When the latter are used, the pH ofthe halogenation reaction mixture is controlled below about pH 8 andpreferably between about 5 and about 7 by the simultaneous addition of amineral acid. If bromine or chlorine is used in the halogenationreaction either directly or as bromine or chlorine water, the pH of thehalogenation reaction mixture is maintained in the above range by theaddition of alkali metal carbonates or hydroxides. The preferred pHrange is utilized to maintain reasonable reaction rates.

The amount of HOX required in the halogenation process is about 1 toabout 1.1 moles per mole of the compound of formula (IA). If asubstantially greater ratio of HOX than 1.1 moles per mole of thecompound of formula (IA) is utilized, it will not affect formation ofthe product but is uneconomical. If substantially less than one mole isemployed, the reaction will not proceed to completion.

The temperature of the halogenation process is usually in the range fromabout 0° to 50° C. to avoid premature decarboxylation prior tohalogenation of the compound and to avoid excessive loss of halogenwhich is in equilibrium with the hypohalous acid. Ambient temperaturesare preferred as a matter of practicality and to keep side reactions toa minimum. After addition of the HOX reactant is complete, the reactionis monitored by periodic sampling and analysis by NMR. Thecharacteristic NMR frequency of the methylene protons will shift fromhigh field in the case of the compound of formula (IA) to a lower fieldas the halogenated compound of formula (V) is formed in the reactionmixture. When the desired degree of halogenation is obtained, thecompound of formula (V) which is water soluble is isolated in its acidform by conventional methods involving acidification of the reactionmixture and extraction of the compound with a suitable organic solventsuch as ethyl ether.

CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO AMIXTURE OF CIS AND TRANS ACONITIC ACID

The compounds of formula (V) may be "dehydrohalogenated" withoutisolation either under strongly alkaline conditions to produce apropene-1,1,2,3-tetracarboxylate which upon acidification decarboxylatesto form aconitic acid (i.e. cis and trans aconitic acids) or underacidic aqueous conditions to produce directly a mixture of isocitricacid and alloisocitric acids and the lactones thereof. In both cases the"dehydrohalogenation" appears to proceed through an initial substitutionof OH for the halogen followed by elimination of water under thealkaline conditions or decarboxylation under the acidic conditions.

In the case of "dehydrohalogenation" of the compound of formula (V), anaqueous solution of the formula (V) compound is neutralized and madealkaline to a pH of about 10 to about 12.6, preferably from about 11 toabout 12, by the slow addition of an alkaline earth metal hydroxideselected from the group Ca(OH)₂, Sr(OH)₂ and Pa(OH)₂, preferablyCa(OH)₂. The alkaline solution is heated at about 25° C. to about 100°C. preferably about 50° C. to about 70° C. until "dehydrohalogenation"is complete, i.e. about 1/2 hour to 2 hours. The "dehydrohalogenation"is prereferably monitored by NMR. This is done by sampling the solution,treating with excess Na₂ CO₃, filtering the insoluble calcium carbonatethat forms, evaporating the filtrate and examining the residue by NMR.The reaction is stopped at maximum formation of the propene 1,1,2,3tetracarboxylate salt (VI) by observing the intensity of the chemicalshift for the methylene protons on carbon 3 at about 3.34δ. Thetetracarboxylate calcium salt in the reaction mixture is then treatedwith dilute mineral acid to liberate the free acid which then undergoesdecarboxylation to produce a mixture of cis and trans aconitic acids.The reaction scheme for the above described preparation of cis/transaconitic acids is thus as follows: ##STR14##

CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO AMIXTURE OF CIS AND TRANS ACONITIC ACID, ISOCITRIC ACID, ALLOISOCITRICACID AND THE LACTONES OF ISOCITRIC ACID AND ALLOISOCITRIC ACID

In the case where Sr(OH)₂ is used to "dehydrohalogenate" the compoundsof structure V described above, it is possible to obtain a mixture ofstrontium salts of propene-1,1,2,3-tetracarboxylic acid and the1-hydroxypropane-1,1,2,3-tetracarboxylic acid intermediate by followingthe reaction by NMR and stopping the reaction at the maximum formationof the propene-1,1,2,3-tetracarboxylate species (i.e. maximum intensityof the chemical shift for the methylene protons on carbon 3). Onacidification with an aqueous solution of a mineral acid, e.g.hydrochloric acid, or treatment with a cation exchange resin in its acidcycle, decarboxylation occurs to give a mixture of cis and transaconitic acid, isocitric acid, alloisocitric acid and the lactones ofisocitric acid and alloisocitric acid. The mixture of products may beisolated by conventional techniques such as solvent extraction or byevaporation of the water followed by extraction with a suitable solventsuch as acetone and subsequent evaporation of the acetone extract.

In the case where Ba(OH)₂ is used to "dehydrohalogenate" the compoundsof structure V described above in the pH range 11-12, the reaction formspredominantly the 1-hydroxypropane-1,1,2,3-tetracarboxylate species asthe barium salt. On acidification with an aqueous solution of a mineralacid, e.g. hydrochloric acid, or treatment with a cation exchange resinin the acid cycle, decarboxylation occurs to give a mixture of isocitricacid, alloisocitric acid and the lactones of isocitric acid andalloisocitric acid together with some cis and trans aconitic acid.

CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO AMIXTURE OF ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE LACTONES THEREOF

In the special case where the compounds of structure V are reacted withMg(OH)₂ in aqueous medium, a pH of only about 8-9 is achievable. Underthese conditions and between temperatures of about 25° C. and about 105°C., preferably from 90°-105° C., the halogen atom is substituted by ahydroxyl group with simultaneous decarboxylation as well assaponification (with sufficient Mg(OH)₂) to give a mixture of themagnesium salts of isocitric acid and alloisocitric acid. The lattersalts may then be converted into the acid and lactone forms by eithertreatment with a suitable cation exchange resin or acidification withmineral acid and isolation by conventional techniques such as solventextraction or evaporation of the water present followed by extraction ofthe residue with a solvent such as acetone and subsequent evaporation ofthe acetone extract.

Alternatively, the compounds of structure V may be treated under weaklyalkaline conditions of about pH 8-9 utilizing an aqueous solutioncontaining the stoichiometric amount (one equivalent per mole of V) ofalkali metal hydroxide or alkaline earth metal hydroxide at temperaturesbetween 25° C. and 75° C. Under these conditions a novel β-lactone esterof the following structure is obtained: ##STR15## wherein R, R₁ and R₂are as previously defined. In place of the alkali metal or alkalineearth metal hydroxides, a weak organic base such as pyridine ortriethylamine may also be reacted with compounds of structure V underanhydrous conditions to produce the same product (i.e. compound VII).

In another embodiment, an aqueous solution of an alkali metal carbonatewith or without an auxiliary organic base such as pyridine is reactedwith a compound of formula V to produce a compound of formula VIII:##STR16## wherein R, R₁ and R₂ as previously defined and M is an alkalimetal cation selected from the group lithium, sodium and potassium.

The compound of structures (VII) and (VIII) may be readily hydrolyzed byheating with the appropriate amount of aqueous solution of an alkalimetal hydroxide, alkali metal carbonate or an alkaline earth metalhydroxide at a pH of about 9-11 and preferably between about 9 and 10 toproduce tetracarboxylate salts having the following structure: ##STR17##wherein M₂ is Li, Na or K or an alkaline earth metal cation selectedfrom the group Ca, Sr and Ba and x is 1 or 2 and corresponds to thevalence of the cation M₂.

The compounds of formula (IX) wherein M₂ is Ca, Sr or Ba may also betreated with a solution of an alkali metal carbonate to produce thecorresponding alkali metal salts (i.e. formula (IX) wherein M₂ is Li, Naor K and x=1. The alkali metal salts of formula (IX) are useful asdetergent builders and metal ion sequestrants.

The compounds of formula (IX) may each be converted into a mixture ofisocitric acid, alloisocitric acid and the lactones of isocitric acidand alloisocitric acid by acidification with a dilute solution of amineral acid such as hydrochloric acid, whereby decarboxylation occursto produce the said mixture of products.

In another preferred embodiment the halogenated species of formula (V)may be heated with an aqueous solution of mineral acid, e.g. refluxingwith 10% hydrochloric acid for about 1 to about 16 hours tosimultaneously hydrolyze the ester groups, dehydrohalogenate anddecarboxylate the compound to produce a mixture of isocitric acid,alloisocitric acid and the lactones thereof. The temperature of reactionis about 25° C. to about 110° C., preferably about 90° C. to 100° C. Thereaction is run for a sufficient amount of time to result in the desiredend product, usually about 6 hours to about 10 hours.

The reaction scheme thus is the same as that for aconitic acid up to theproduct of formula (V). The remaining sequences is as follows: ##STR18##

Representative compounds of formula (I) prepared according to theprocess of the invention include

1--Calcium Bis[Methyl α-(dimethyl malonyl)succinate] ##STR19## 2--Ethylsodium α-(diethyl malonyl)succinate ##STR20## 3--Methyl hydrogenα-(diethyl malonyl)succinate ##STR21## 4--Ethyl hydrogen α-(dimethylmalonyl)succinate ##STR22## 5--Methyl hydrogen α-(1-nitroethyl)succinate##STR23## 6--Methyl hydrogen α-(acetyl carboethyl methinyl)succinate##STR24## 7--Methyl hydrogen α-(cyanobenzyl)succinate ##STR25##8--Methyl hydrogen α-(cyano carboethoxy methinyl)succinate ##STR26##9--Methyl sodium α-(methyl sodium malonyl)succinate ##STR27##10--Potassium butane-1,2,2,4-tetracarboxylic methyl ester-3-carboxylate##STR28##

Representative compounds of formula V are as follows:

1--Methyl hydrogen α-(dimethyl chloromalonyl)succinate ##STR29##2--Ethyl hydrogen α-(diethyl chloromalonyl)succinate ##STR30## 3--Methylhydrogen α-(diethyl-2-chloromalonyl)succinate ##STR31## 4--Ethylhydrogen α-(dimethyl chloromalonyl)succinate ##STR32## 5--Methylhydrogen α-(dimethyl bromomalonyl)succinate ##STR33##

Representative compounds of formulas (VI), (VII), (VIII) and (IX)obtained from the halogenated compounds of formula (V) are as follows:

1--Tetrasodium propene-1,1,2,3-tetracarboxylate ##STR34## 2--Methylhydrogen α-(dimethyl hydroxymalonyl)succinate β-lactone ##STR35##3--Ethyl hydrogen α-(diethyl hydroxymalonyl)succinate β-lactone##STR36## 4--Ethyl hydrogen α-(diethyl hydroxymalonyl)succinate##STR37## 5--Dicalcium 1-hydroxy propane-1,1,2,3-tetracarboxylate##STR38## 6--Tetrasodium propane-1-hydroxy-1,1,2,3-tetracarboxylate

The following examples will more fully illustrate the embodiments ofthis invention. All parts and proportions referred to herein and in theappended claims are by weight unless otherwise indicated.

EXAMPLE I A. PREPARATION OF SODIUM METHYL MALEATE

One mole of maleic anhydride is dissolved in 1000 ml methanol and 0.5mole of sodium carbonate is added. The solution is filtered and themethanol is distilled off under pressure. After drying the product in avacuum oven, 152 g of sodium methyl maleate is obtained.

B. PREPARATION OF CALCIUM BIS(METHYL MALEATE) ##STR40##

One mole of maleic anhydride is dissolved with stirring in 1000 mlmethanol at 50°-60° C. The mixture is cooled to 25° C. and with the aidof a pH meter, the pH is adjusted to 8.6 with calcium hydroxide whilemaintaining the temperature below 25° C. with an ice bath. 149 g ofcalcium bis(methyl maleate) is recovered by crystallizing out ofmethanol followed by drying in a vacuum oven.

C. PREPARATION OF LITHIUM METHYL MALEATE

Twenty grams of maleic anhydride is dissolved in 200 mls methanol, 4.8grams (0.2 moles) lithium hydroxide is added. The mixture is stirreduntil all the lithium hydroxide dissolves (at this point the pH reads7.0). To the solution is added acetone and the solid is filtered anddried. 23 grams product is obtained.

D. PREPARATION OF POTASSIUM METHYL MALEATE

46.5 grams (0.46 mole) maleic anhydride is dissolved in 500 mlsmethanol. 36 g K₂ CO₃ is added to a pH of 8.5-8.6, the solution isfiltered and evaporated to dryness. 77.6 grams of product is obtained.Purity=96.4% by NMR analysis.

E. PREPARATION OF SODIUM ETHYL MALEATE

Fifty-seven grams (0.57 moles) maleic anhydride is dissolved in 500 mlsethanol. With the aid of a pH meter the pH is adjusted to 8.5-8.6 withsodium carbonate. The solution is evaporated on the roto evaporator anddried in a vacuum oven. Ninety-four grams (0.57 moles) of product havinga purity of 99.4% (NMR analysis) is obtained.

EXAMPLE II PREPARATION OF METHYL HYDROGEN α-(DIMETHYL MALONYL)SUCCINATE##STR41## Method A

Into a 500 ml, one neck flask equipped with magnetic stirrer is placed100 grams sodium methyl maleate and 350 grams dimethyl malonate. Thereaction temperature is maintained at 100°-105° C. for 5 hours. Theexcess malonate is distilled off under vacuum and the residue isextracted with ether:acetone (5:1) to remove unreacted malonate andthereby leaving a gummy residue of the sodium salt of the titlecompound. The latter is then dissolved in water, acidified with 1:1sulfuric acid and the resulting liquid organic layer is separated fromthe water layer. On standing this liquid crystallizes. The total solid,180 grams, is extracted with hexane to remove any malonate and the solidis dried. Yield: 153 grams. The water soluble fraction from above isevaporated to dryness and extracted with hexane. Ten grams of additionalproduct is obtained in this manner. Total yield: 163 grams (94% oftheoretical).

Method B

Fifty grams sodium methyl maleate is mixed with 200 grams dimethylmalonate in a 500 ml one neck flask equipped with a magnetic stirrer.The temperature is maintained at 100°-105° C. for 4 hours, then theexcess malonate is distilled off under vacuum. The viscous liquidobtained is dissolved in water and 0.33 moles sulfuric acid in 25 mlswater is added. The liquid separates and crystallizes on standing. Theentire solution including the crystals is filtered and the product iswashed with water leaving a white solid (23 grams). The water layer isextracted with ether and the ether distilled off. On standing theresidue crystallizes; yield: 12.5 grams, m.p. 101.5° C. Total yield ofproduct: 35.5 grams.

Method C

24.3 grams (0.145 mole) potassium methyl maleate is added to 100 g ofdimethyl malonate. The mixture is heated to 110°-115° C. for 4-5 hours.Complete solution is attained in 3-4 hours. The reaction solution isthen distilled under pressure to remove excess dimethyl malonate. Thedistillation residue is dissolved in 200 mls water and acidified with 15g conc. HCl in 25 mls water. The resulting organic layer is extractedwith ethyl ether and the ethereal extract evaporated to give a residueof 42 g (theoretical: 39 grams). The product crystallizes on standing.

The structure of the products obtained by the three methods is confirmedby NMR analysis (CDCl₃) to correspond to the title compound: ##STR42##CH₂ (a) ABX multiplet, two peaks, one at 2.76δ, one at 2.86δ

Ch(b) multiplet, 3.44-3.70δ

Ch₃ (c) singlet at 3.70δ

Ch₃ (d) singlet at 3.76δ

Ch(e) doublet centered at 3.99δ.

EXAMPLE III PREPARATION OF METHYL HYDROGEN α-(DIETHYL MALONYL)SUCCINATE##STR43##

Ninety grams of sodium methyl maleate is reacted with 200 grams ofdiethyl malonate at 100°-110° C. for four hours. After the reactionmixture is cooled to 25° C., 1000 mls of water is added and theunreacted diethyl malonate layer is separated. The aqueous layer isacidified with a mixture of 61 g of conc. hydrochloric acid and 50 mlswater and the organic layer is separated. The organic layer is dissolvedin ether and washed with water to remove dissolved methyl hydrogenmaleate. The ether is then distilled off, obtaining 95 grams (55% yield)of product. The structure is confirmed by NMR analysis (CDCl₃):##STR44## CH₃ (a) triplet centered at 1.25δ CH₂ (b) doublet (ABX) onepeak at 2.75δ, one at 2.83δ

Ch(c) multiplet, 3.43-3.78δ

Ch₃ (d) singlet, 3.67δ

Ch(e) doublet centered at 3.92δ

Ch₂ (f) quartet centered at 4.19δ.

EXAMPLE IV PREPARATION OF ETHYL HYDROGEN α-(DIETHYL MALONYL)SUCCINATE##STR45##

One hundred grams of sodium ethyl maleate is reacted with 500 grams ofdiethyl malonate at 100°-110° C. for 5 hours. The solution is cooled andis mixed with 1000 mls water. The aqueous layer is separated andacidified with 110 grams of 6.5 N hydrochloric acid. The liquid organiclayer which separates is dissolved in ether and extracted twice withwater to remove ethyl hydrogen maleate. After evaporation of the ether,a residue of 140 g (46% yield) of the title compound is obtained. Thestructure is confirmed by NMR analysis (CDCl₃): ##STR46## CH₃ (a)triplet, 1.1-1.45δ CH₂ (b) doublet centered at 2.67δ

Ch(c) multiplet centered at 3.60δ

Ch(d) doublet centered at 3.92δ

Ch₂ (e) quartet centered at 4.15δ

Ch₂ (f) quartet centered at 4.20δ.

EXAMPLE V PREPARATION OF ETHYL HYDROGEN α-(DIMETHYL MALONYL)SUCCINATE##STR47##

Twenty five grams (0.15 mole) of sodium ethyl maleate (of 99.4% purity)is mixed with 100 grams of dimethyl malonate and the solution heated at100°-107° C. for 6 hours. The solution is then evaporated under reducedpressure to remove excess dimethyl malonate. The distillation residue isdissolved in 200 mls water and acidified with 40 g of 4.5 N hydrochloricacid. The product which separates as a liquid, is extracted with 100 mlschloroform and the chloroform extract is distilled under reducedpressure. Forty five grams of a liquid product is obtained as a residue.NMR analysis (CDCl₃) is consistent with the title compound containingtraces of dimethyl malonate: ##STR48## CH₃ (a) triplet centered at 1.22δCH₂ (b) ABX doublet, 2.55-2.87δ

Ch(c) ABX multiplet, 3.15-3.57δ

Ch₃ (d) singlet, 3.75δ

Ch(e) doublet centered at 3.93δ

Ch₂ (f) quartet centered at 4.12δ.

EXAMPLE VI PREPARATION OF METHYL HYDROGEN α-(ACETYL CARBOETHOXYMETHINYL)SUCCINATE ##STR49##

Into a 100 ml, one neck flask equipped with a magnetic stirrer is placed10 grams sodium methyl maleate and 40 grams ethyl acetoacetate. Themixture is heated to 110° C. for 45 minutes. Water, 200 mls, is thenadded to the reaction mixture and the upper layer, consisting of ethylacetoacetate, is removed. The water layer is acidified with a mixture of7 grams conc. H₂ SO₄ and 10 mls water. The liquid that separates isextracted with ether and the ether extract is distilled in vacuo toleave a viscous residue. The residue is extracted 4-5 times with hothexane to remove ethyl acetoacetate and leaving behind 14 grams (77.8%of theoretical) of the title compound (neutralization equivalent found,264). NMR analysis (CDCl₃) of the product confirms the structure andshows the product to consist of a 58:42 weight ratio of keto:enol forms:##STR50## CH₃ (a) triplet centered at 1.27δ CH₃ (b) singlet, 2.28δ

Ch₂ (c) ABX multiplet, 2.57-2.88δ broad

Ch(d) multiplet, 3.46-3.81δ

Cooch₃ (e) singlet, 3.60δ

Ch(f) doublet, 3.90-4.09δ

Cooch₂ (g) quartet centered at 4.16δ. ##STR51## CH₃ (a') tripletcentered at 1.25δ CH₃ (b') singlet at 1.82δ.

All other spectral assignments are the same as for the keto form.

EXAMPLE VII A. PREPARATION OF LITHIUM METHYL α-(CYANO CARBOETHOXYMETHINYL)SUCCINATE ##STR52##

Fifty grams (0.38 mole) of lithium methyl maleate is dissolved in amixture of 150 grams ethyl cyanoacetate and 100 grams DMF (dimethylformamide) at 80°-90° C. The temperature is then raised to 100°-105° C.for 45 minutes. The solution is evaporated in vacuo to remove excesssolvents and the residue is extracted twice with 500 mls ether to leave96 grams of the title compound as a gummy residue. The structure isconfirmed by NMR analysis (D₂ O): ##STR53## CH₃ (a) triplet centered at1.15δ CH₂ (b) multiplet, 2.69-3.05δ

Ch(c) multiplet, 3.25-3.48δ

Ch₃ (d) singlet, 3.68δ

Ch(e) hidden under CH₂ (f) group

Ch₂ (f) quartet centered at 4.24δ.

B. PREPARATION OF METHYL HYDROGEN α-(CYANOCARBOETHOXY METHINYL)SUCCINATE##STR54##

Ninety six grams of the product obtained above in VII(A) is dissolved inwater and a mixture of 38 grams conc. hydrochloric acid in 50 mls wateris added to the solution. The product which separates is extracted withether. Evaporation of the ether extract yields 74 grams of productcontaining traces of ethyl cyanoacetate and DMF. NMR analysis (CDCl₃)confirms the structure: ##STR55## CH₃ (a) triplet centered at 1.33δ CH₂(b) multiplet at 2.98-3.08δ

Ch(c) multiplet at 3.35-3.70δ

Ch₃ (d) singlet, 3.72δ

Ch(e) doublet centered at 4.25δ

Ch₂ (f) quartet centered at 4.30δ.

EXAMPLE VIII PREPARATION OF METHYL HYDROGEN α-(CYANOBENZYL)SUCCINATE##STR56##

Into a 200 ml, one-neck flask is placed 35 grams of sodium methylmaleate (0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and80 g(1.1 moles) dimethyl formamide. The reaction mixture is heated to125°-140° C. for five hours and then distilled in vacuo. The residue isextracted three times with 300 ml ether. The solid (56 grams) is thendissolved in water and acidified with 23 grams conc. HCl in 50 mlswater. The liquid that separates out is dissolved in ether and washedwith water to remove unreacted starting materials. The ether isdistilled off to give a residue of 50 grams of product (yield: 88°). Thestructure is verified by NMR (in CDCl₃): ##STR57## CH₂ (a) ABX multipletat 2.50-3.00δ CH(b) multiplet, 3.30-3.56δ

Ch₃ (c) singlet, 3.67δ

Ch(d) multiplet, 4.20-4.60δ

Ch(e) (phenyl) at 7.35δ.

EXAMPLE IX PREPARATION OF METHYL HYDROGEN δ(1 NITROETHYL)SUCCINATE##STR58##

Into a 100 ml, one neck flask is placed 10 grams of sodium methylmaleate, 60 mls N,N-dimethyl formamide (DMF) and 40 grams nitroethane.The solution is heated at 60° C. for two hours and then partiallydistilled in vacuo to remove the DMF and nitroethane. The residue, byNMR analysis (D₂ O), has the following structure: ##STR59## CH₃ (a)doublet of doublets [ one centered at 1.44δ; one centered at 1.57δ

Ch₂ (b) multiplet, 2.5-2.72δ

Ch(c) multiplet centered at 3.25δ

Ch₃ (d) singlet, 3.65δ

Ch(e) multiplet, 4.77-5.1δ.

The residue from above is dissolved in water and acidified with 7 mlsconc. hydrochloric acid. The water is distilled off and the residue isextracted with acetone. The acetone is evaporated and the liquid residueis extracted with hexane to remove dissolved DMF. The residue is thentriturated with ether, filtered and the ether is removed under vacuum.Five grams (14% yield) of product is obtained. The structure isconfirmed by NMR analysis (CDCl₃): ##STR60## CH₃ (a) doublet of doublets[ one centered at 1.56δ; one centered at 1.78δ

Ch₂ (b) multiplet, 2.6-2.9δ

Ch(c) multiplet, 3.32-3.64δ

Ch₃ (d) singlet, 3.65δ

Ch(e) multiplet centered at 5.0δ.

EXAMPLE X PREPARATION OF SODIUM METHYL α-(METHYL SODIUMMALONYL)SUCCINATE ##STR61## as follows:

One mole of dimethyl malonate is dissolved in 100 mls methanol and 1/2mole of NaOH dissolved in 100 mls of methanol is added. The solution isstirred for 6 hours, the methanol is evaporated off and the solidfiltered and washed with ether. One mole of sodium methyl malonate isrecovered.

Twenty grams of the sodium methyl malonate (0.14 mole) and 15 grams (0.1mole) sodium methyl maleate are mixed with 100 grams of dimethylformamide (DMF) and the mixture heated at 115°-118° C. for 1/2 hourwhile stirring the mixture. The reaction mixture is then cooled and 100mls of acetone is added to extract out DMF. The solid is trituratedfirst with 400 mls of ether and then with 400 mls of 1:1 acetone:ether.Twenty six grams (73% yield) of product is obtained. NMR analysis of theproduct is D₂ O confirms the structure and in addition shows thepresence of some fumarate and malonate: ##STR62## H(a) 3.55-3.80δ H(b+c)3.10-3.6δ

Ch₃ (d+e) 3.7δ.

EXAMPLE XI PREPARATION OF METHYL HYDROGEN TETRAMETHYLBUTANE-1,2,2,4-TETRACARBOXYLATE-3-CARBOXYLIC ACID ##STR63##

A mixture of 16.8 g (0.1 mole) of potassium methyl maleate and 50 g oftrimethyl ethane-1,1,3-tricarboxylate is heated at 140° C. for 5 hours.The reaction mixture is cooled and mixed with 200 ml of water and 200 mlof ethyl ether. After shaking the mixture, the water layer, whichcontains the potassium salt of the title compound, is separated andacidified with 10 g of concentrated hydrochloric acid. The acidifiedmixture is extracted with ethyl ether and the ether layer is evaporatedto give 16 g of the title compound. The structure of the compound isconfirmed by NMR (CDCl₃): ##STR64## CH₂ (a+a') multiplet at 2.6-2.9CH(b) multiplet at 2.9-3.14

Ch₃ (c) three singlets at 3.65-3.9.

EXAMPLE XII PREPARATION OF METHYL HYDROGEN α-(DIMETHYLCHLOROMALONYL)SUCCINATE ##STR65##

Thirteen grams (0.05 moles) of the product prepared in Example II, i.e.methyl hydrogen α-(dimethyl malonyl)succinate, is dissolved in 150 mlsof water. Sodium hypochlorite, 70 grams of a 5.25% by weight solution,is added slowly while stirring the solution during a 15 minute perioduntil the pH rises to 7.0. The solution is then acidified is thenacidified to pH 1.9 and is extracted with ether. The ether extract isevaporated to give fifteen grams of the title compound as a liquid. NMRanalysis (CDCl₃) confirms the structure: ##STR66## CH₂ (a) multipletconsisting of a doublet and singlet 2.83-3.04δ

Ch(b) doublet of doublets, 4.04-4.30δ

Cooch₃ (c) singlet at 3.74δ

Cooch₃ (d) singlet at 3.87δ:

EXAMPLE XIII PREPARATION OF METHYL HYDROGEN α-(DIETHYLCHLOROMALONYL)SUCCINATE ##STR67##

Into a beaker is placed 90 grams of the product prepared in Example III,i.e. methyl hydrogen α-(diethyl malonyl)succinate, and 200 mls water.500 mls of NaOCl solution (5.25% by weight) is added slowly during a 1/2hour period to a pH of 7.0. The solution is then acidified with dilutehydrochloric acid (10%), to a pH of 1.0 and extracted with ether. Theether extract is evaporated to give 95 g (95% yield) of the titlecompound as a syrupy residue. The structure is confirmed by NMR analysis(CDCl₃): ##STR68## CH₃ (a) triplet centered at 1.28δCH₂ (b) ABXmultiplet [ doublet centered at 2.91δ; singlet at 2.82δ

Ch₃ (c) singlet at 3.70δ

Ch(d) multiplet, 3.95-4.23δ

Ch₂ (e) quartet centered at 4.28δ.

EXAMPLE XIV PREPARATION OF ETHYL HYDROGEN α-(DIETHYLCHLOROMALONYL)SUCCINATE ##STR69##

One hundred grams of the compound prepared in Example IV, i.e. ethylhydrogen α-(diethyl malonyl)succinate, is mixed with 300 mls water. Fivehundred mls of (5.25% by weight) sodium hypochlorite is added during 45minute period to a pH of 7.0. The solution is then acidified to a pH of1 with dilute (10%) hydrochloric acid and the product which separates isextracted with ether. The ether extracts are evaporated to give 92 g(82% yield) of the title product as a syrupy residue. The structure isconfirmed by NMR analysis (CDCl₃): ##STR70## CH₃ (a) triplet centered at1.26δ CH₃ (b) triplet centered at 1.29δ

Ch₂ (c) ABX multiplet one peak at 2.81δ, a doublet centered at 2.93δ

Ch(d) mutliplet, 4.0-4.3δ

Ch₂ (e) superimposable quartets (2 pairs 4.05-4.5δ).

EXAMPLE XV PREPARATION OF ETHYL HYDROGEN α-(DIMETHYLCHLOROMALONYL)SUCCINATE ##STR71##

Seventy grams of the compound prepared in Example V, i.e. ethyl hydrogenα-(dimethylmalonyl)succinate is dissolved in 200 mls water. Five hundredgrams of 5.2% sodium hypochlorite is then added slowly over a 30 minuteperiod while maintaining the pH of the reaction mixture in the range 6-7by the simultaneous addition of dilute hydrochloric acid. The reactionmixture is then acidified to a pH of 2 with concentrated hydrochloricacid and extracted with ethyl ether. After separation and evaporation ofthe ethyl ether layer, there is obtained 73 g (96.6% yield) of the titlecompound as a residue. The structure is confirmed by NMR analysis(CDCl₃): ##STR72## CH₃ (a) triplet centered at 1.22δ CH₂ (b) ABXmultiplet at 2.72-2.97δ

Ch₃ (c) singlet at 3.80δ

Ch(d) ABX multiplet at 3.80-4.00δ

Ch₂ (e) quartet centered at 4.15δ.

EXAMPLE XVI PREPARATION OF METHYL HYDROGEN α-(DIMETHYLBROMOMALONYL)SUCCINATE ##STR73##

To 3.3 grams (0.0125 mol) of the compound of Example II, i.e. methylhydrogen α-(dimethyl malonyl)succinate, dissolved in 100 mls water, isslowly added over a 15 minute period 27 mls of sodium hypobromitesolution (4.2% by weight) to a pH of 7.0. After 20 minutes, the solutionis acidified to a pH of 1.0 with dilute (5%) hydrochloric acid andextracted with ether. The ether extract is evaporated to give 3 g (75%yield) of the title compound as a syrupy residue. The structure isconfirmed by NMR analysis (CDCl₃): ##STR74## CH₂ (a) doublet [ one peakat 2.93δ; one peak at 3.03δCH(b) triplet centered at 4.10δ

Ch₃ (c) split into 2 doublets centered at 3.17δ

Ch₃ (d) single, 3.85δ

EXAMPLE XVII PREPARATION OF METHYL HYDROGEN α-(DIMETHYLHYDROXYMALONYL)SUCCINATE β-LACTONE ##STR75##

Twenty six grams of the compound prepared in Example II, i.e. methylhydrogen α-(dimethyl malonyl)succinate, is dissolved in 150 mls water. Asolution of 5.25% sodium hypochlorite is then added slowly until the pHof the reaction mixture increases to 7.0. The water medium is thenremoved in vacuo at 40° C. to leave a yellow residue which is taken upin chloroform and filtered. The chloroform filtrate is evaporated togive a purified residue which is then redissolved in water and passedthrough a cation exchange resin in the acid form. The water layer in theeluate is separated and evaporated to give 25 grams of ##STR76## as aresidue. The organic layer (2 g) from the eluate corresponds to thelactone product (confirmed by infrared and NMR analysis). Infraredanalysis shows a peak for a four membered lactone at 5.4μ. The NMRanalysis (CDCl₃) is as follows: ##STR77## CH₂ (a) ABX multiplet, onepeak at 3.07δ one doublet centered at 2.94δ

Ch(b) multiplet centered at 4.66δ

Cooch₃ (c) singlet at 3.82δ

Cooch₃ (d) singlet at 3.96δ

Cooch₃ (e) singlet at 4.00δ.

EXAMPLE XVIII PREPARATION OF ETHYL HYDROGEN α-(DIETHYLHYDROXYMALONYL)SUCCINATE β-LACTONE

Procedure A ##STR78##

Ten grams (0.032 mole) of the compound prepared in Example XIV, i.e.ethyl hydrogen α-(diethyl chloromalonyl)succinate is dissolved in 100mls of ethanol and Ca(OH)₂ is added until the pH reaches 8.6. Theethanol is removed under vacuum at 45° C., 100 mls of pyridine is addedand the resulting solution is heated at 90° C. for one hour. Thepyridine is removed in vacuo and the residue is extracted with ethylether. Evaporation of the ether extracts gives 8 g (84% yield) of thetitle compound. The structure is confirmed by NMR analysis (CDCl₃):##STR79## CH₃ (a) superimposed triplets, 1.0-1.5δ CH₂ (b) ABX multiplet,2.75-3.00δ

Ch₂ (c) superimposed quartets, 3.92-4.50δ

Ch(d) ABX multiplet, 4.50-4.73δ.

Procedure B

Six grams of the compound prepared in Example XIV, i.e. ethyl hydrogenα-(diethyl chloromalonyl)succinate, is dissolved in 50 mls of chloroformand 100 grams of triethyl amine is added. The solution is stirred at40°-50° C. for 45 minutes. The excess amine and chloroform are removedin vacuo and the residue is extracted with ether. The ether extracts arethen evaporated to dryness to give 5 grams of the title compound. Thestructure is confirmed by NMR analysis (CDCl₃).

EXAMPLE XIX PREPARATION OF ETHYL HYDROGEN α-(DIETHYLHYDROXYMALONYL)SUCCINATE ##STR80##

Five grams (0.016 mole) of the compound prepared in Example XIV, i.e.ethyl hydrogen α-(diethyl chloromalonyl)succinate, is dissolved in 100mls of water and Na₂ CO₃ is added to a pH of 8.6. Sixty mls of pyridineis added and the solution is heated at 80° C. for one hour (at thispoint the pH is 7.0). The solvents (H₂ O+pyridine) are removed undervacuum and the residue is extracted with acetone. The acetone extract isevaporated to leave a residue of the sodium salt of the title compound.The structure is confirmed by NMR analysis (D₂ O): ##STR81## CH₃ (a)superimposed triplets at 1.1-1.47δ CH₂ (b) ABX multiplet at 2.5-2.8δ

Ch(c) ABX multiplet at 3.7-4.1δ

Ch₂ (d) superimposed quartets at 4.0-4.5δ.

The above salt is dissolved in 100 mls of water and the pH is adjustedto 1.0 with dilute hydrochloric acid (10%). The acidified solution isthen extracted with ethyl ether and the ether extract is evaporated toyield 3.5 g (70% yield) of the title compound. The structure isconfirmed by NMR analysis (CDCl₃): ##STR82## CH₃ (a) superimposedtriplets at 1.12-1.50δ CH₂ (b) ABX multiplet at 2.56-2.94δ

Ch(c) ABX multiplet at 3.74-4.02δ

Ch₂ (d) superimposed quartets at 3.98-4.52δ.

EXAMPLE XX PREPARATION OF METHYL HYDROGEN α-(DIMETHYLHYDROXYMALONYL)SUCCINATE ##STR83##

A mixture of 15 g (0.05 mole) of the compound prepared as in ExampleXII, i.e. methyl hydrogen α-(dimethyl chloromalonyl)succinate, and 200ml of water is neutralized to a pH of 9.0 by the addition of 2.8 g(0.026 mole) of sodium carbonate. The resulting solution is refluxed for30 minutes whereby the pH drops to about 2. The solution is evaporatedand the residue extracted with acetone. The acetone solution is filteredand evaporated to yield 9 g of a syrupy product corresponding to thetitle compound. The structure is confirmed by NMR analysis (CDCl₃):##STR84## CH₂ (a) ABX multiplet at 2.60-3.00δ CH(b) hidden

Ch₃ (c) singlet at 3.76δ

Ch₃ (d) singlet at 3.90δ.

EXAMPLE XXI PREPARATION OF α-(2-HYDROXY DISODIUM MALONYL)DISODIUMSUCCINATE ##STR85##

Ten grams (0.03 mole) of the compound prepared in Example XIV, i.e.ethyl hydrogen α-(diethyl chloromalonyl)succinate is mixed with 75 mlwater and 4.4 g (0.06 mole) of Ca(OH)₂. After 15 minutes an additional 3grams of Ca(OH)₂ is added to maintain the pH at 9.5-10.0. The resultingmixture is heated at 60°-70° C. for 4 hours while stirring andmaintaining the pH at 9.5-10.0 by further addition of Ca(OH)₂ asrequired. Sodium carbonate, 0.1 mole, is then added and the reactionmixture is stirred at 60°-70° C. for 15 minutes. The solution isfiltered to remove CaCO₃ and the pH of the filtrate is adjusted to 9.0with dilute hydrochloric acid. After evaporation of the water, a residueof 9 g of the title compound containing traces of sodium chloride isobtained. The structure of the product is confirmed by NMR analysis (D₂O): ##STR86## H(a) 2.25-2.7 H(b) 3.0-3.9

EXAMPLE XXII PREPARATION OF ISOCITRIC AND ALLOISOCITRIC ACID LACTONES

Procedure A ##STR87##

One gram of the product prepared in Example XXI above is acidified withdilute HCl (10% (with liberation of CO₂) and evaporated to dryness invacuo. The product consists of a mixture of isocitric and alloisocitricacid lactones by NMR analysis (D₂ O): ##STR88## H(a) ABX multiplet at2.94-3.28δ H(b) ABX multiplet at 3.78-4.19δ

H(c) doublet at 5.38-5.58δ

H(c') doublet at 4.3-4.5δ (traces of isocitric acid and alloisocitricacid).

Procedure B

Fifty grams of the compound prepared in Example XIV, i.e. ethyl hydrogenα-(diethyl chloromalonyl)succinate is dissolved in 100 ml of water towhich 10 ml of concentrated hydrochloric acid has been added. Thesolution is refluxed for 16 hours and then evaporated in vacuo to leave28 g of a solid residue consisting of a 1:1 mixture of the lactones ofisocitric acid and alloisocitric acid (structure determined by NMRanalysis--D₂ O).

EXAMPLE XXIII PREPARATION OF TETRASODIUM PROPENE 1,1,2,3TETRACARBOXYLATE ##STR89##

Twelve grams (0.036 mole) of the product prepared in Example XII, i.e.methyl hydrogen α-(dimethyl chloromalonyl)succinate, is mixed with 200mls water. Ca(OH)₂ is then slowly added at first maintaining the pH at10.0 and then heating to 60°-70° C. until all the ester groups aresaponified. A total of 10 grams of Ca(OH)₂ is added (pH 11.6) and theslurry is stirred for 2-3 hours at 60°-70° C. Thirteen grams of Na₂ CO₃is then added and the mixture is stirred for 15 minutes at 50° C. Theprecipitated CaCO₃ is filtered and the filtrate is evaporated to give 10g of the title compound. The structure is confirmed by NMR analysis (D₂O): --CH₂ -- singlet at 3.34δ.

EXAMPLE XXIV PREPARATION OF 1:1 CIS:TRANS ACONITIC ACID ##STR90##

Nine grams of the product as prepared in Example XXIII, i.e. tetrasodiumpropane-1,1,2,3-tetracarboxylate, is dissolved in 100 mls water andacidified with dilute HCl (10%). Liberation of CO₂ is instantaneous. Theresidue, after evaporation of water, is extracted with acetone. Theacetone is evaporated to leave a residue consisting of a 1:1 by weightmixture of cis:trans aconitic acid. The structure of the product isconfirmed by NMR analysis (D₂ O): ##STR91##

EXAMPLE XXV PREPARATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRICACID AND THE LACTONES THEREOF

Thirty grams (0.1 mole) of the compound prepared in Example XII, i.e.methyl hydrogen α-(dimethyl chloromalonyl)succinate, is mixed with 200ml water. Sodium hydroxide, 20 g (0.5 mole), is added slowly whilemaintaining the temperature at 60° C. and the pH between 9 and 10. Afterheating for 3-4 hours at 60° C., the solution is cooled and acidified toa pH of 1.2 with dilute hydrochloric acid. The solution is thenevaporated in vacuo and the residue remaining is extracted with acetone.The acetone extract is then filtered and the filtrate, evaporated togive a residue of 17 grams of a mixture of 1:1 isocitric acid:alloisocitric acid and the lactones thereof (identified by NMR).

EXAMPLE XXVII PREPARATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRICACID AND THE LACTONES THEREOF

Fifteen grams (0.05 mole) of the product prepared in Example XV, i.e.ethyl hydrogen α-(dimethyl chloromalonyl)succinate is mixed with 200 mlsof water. Magnesium hydroxide, 25 g (0.43 mole), is added slowly whilemaintaining the reaction mixture at 80°-90° C. and the pH at 9.0. Afterrefluxing the reaction mixture for 2 hours, the solution is cooled andthen acidified with 86.2 g of 50% sulfuric acid. The acidified solutionis evaporated to yield a residue which is then extracted with acetone.The acetone extract is filtered and the filtrate evaporated to give 10.4g of residue consisting of a mixture of isocitric acid and alloisocitricacid and the lactones thereof (identified by NMR).

EXAMPLE XXVIII PREPARATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRICACID AND THE LACTONES THEREOF

Fifteen grams (0.05 mole) of the compound prepared in Example XV, i.e.ethyl hydrogen α-(dimethyl chloromalonyl)succinate, is mixed with 200 mlwater. Strontium hydroxide, 24 g (0.2 mole), is then added while heatingthe mixture at 70°-75° C. and while maintaining the pH at 10.0. Thesolution is then cooled and acidified with 120 g of 15% hydrochloricacid. The acidified solution is then evaporated in vacuo to a residuewhich, in turn, is extracted with acetone. The acetone extract isfiltered and the filtrate is evaporated in vacuo to give 7.7 grams ofsyrup consisting of a mixture of isocitric acid, alloisocitric acid andthe lactones thereof (identified by NMR analysis).

This invention has been described with respect to certain preferredembodiments and various modifications and variations in the lightthereof will be suggested to persons skilled in the art and are to beincluded within the spirit and preview of this application and the scopeof the appended claims.

What is claimed is:
 1. A halogenated compound of the general formula##STR92## wherein R, R₁ and R₂ independently represent an alkyl group of1 to 4 carbon atoms; Q₁ is chlorine or bromine; M₁ is hydrogen or alithium, sodium, potassium, magnesium, calcium, strontium, or bariumcation; and x is 1 or 2 and is equivalent to the valency of M₁.
 2. Acompound as defined in claim 1 wherein Q₁ is Cl.
 3. A compound asdefined in claim 2 wherein R, R₁ and R₂ are independently methyl orethyl.
 4. A compound as defined in claim 3 wherein said M₁ is hydrogen.5. A compound as defined in claim 4 wherein said M₁ is a sodium cation.